HRP20000893A2 - Novel 17-halogenated 19-nor steroids, method and intermediates for preparing same, use as medicines and pharmaceutical compositions containing same - Google Patents

Description

This invention relates to new 17-halogenated 19-nor steroid compounds, their preparation process and intermediates, their use as drugs, and pharmaceutical compositions containing them.

Osteoporosis is a pathology characterized by a quantitative and qualitative reduction of bone substance, sufficient to lead to a vertebral or peripheral fracture spontaneously or in cases with minimal trauma. Although the appearance of this disease is the result of numerous factors, menopause in women is the dominant factor in bone loss or osteopenia.

This osteopenia is manifested by the thinning and modification of the spongy structure of the bones, the consequence of which is an increase in the fragility of the skeleton and the risk of fracture. Bone loss increases greatly after menopause due to suppression of ovarian function and before slowing down after the age of 65 reaches 3 to 5% per year.

For therapeutic purposes, hormonal deficiency after menopause can be compensated by the use of hormone replacement therapy, where estrogen plays a major role in preserving bone mass. However, long-term estrogen therapy is sometimes associated with unwanted effects on the genital apparatus (endometrial hyperplasia, breast tumor...), which is the main reason for regression and limits its use.

For this reason, it is desirable to find compounds different from estradiol that have a separate estrogenic activity, namely, in which estrogenic activity occurs at the bone level, but which do not show or have little endometrial hyperplasia activity, and are also not active in the proliferation of breast tumors.

Therefore, the subject of this invention are the compounds shown by the general formula (I):

[image]

in which:

R1 represents a hydrogen atom, (CH2)m-Ar, (CO)-Ar, (CH2)m-Alk or (CO)-Alk radical,

R2 represents a radical obtained from a straight or branched, saturated or unsaturated hydrocarbon containing 1 to 6 carbon atoms

X represents a halogen atom,

Y represents a single bond, O, NH, S, SO, or SO2,

Z represents a hydrogen atom or a halogen atom,

n is equal to the numbers 2, 3, 4 or 5,

R3 and R4, identical or different, represent a hydrogen atom, (CH2)m'-Ar, (CH2)m'-Het or (CH2)m'-Alk group, or R3 and R4 form together with a nitrogen atom, with which they are linked, aromatic or non-aromatic, saturated or unsaturated mono- or polycyclic heterocycle with 3 to 15 members optionally containing 1 to 3 additional hetero atoms selected from oxygen, sulfur and nitrogen, unsubstituted or substituted,

Ar represents a carbocyclic aryl group containing 6 to 18 carbon atoms, Het represents a saturated or unsaturated aromatic or non-aromatic heterocycle containing from 1 to 9 carbon atoms and from 1 to 5 heteroatoms selected from oxygen, nitrogen or sulfur atoms, Alk represents a radical obtained from saturated or unsaturated, linear, branched or cyclic, non-aromatic hydrocarbon and contains from 1 to 12 carbon atoms, radicals Ar, Het or Alk can be substituted or unsubstituted, m and m' represent the numbers 0, 1, 2 or 3, dashed lines represent a possible double bond, as well as their salts with added bases or acids.

Halogen means: iodine, bromine, chlorine or fluorine.

Chlorine or bromine is preferred at position 4.

Fluorine is preferred at position 17.

The following values are understood by (CH2)m, (CH2)m': single bond in the case when m is equal to 0, CH2, (CH2)2 and (CH2)3.

The term Ar, which represents a carbocyclic aryl group with from 6 to 18 carbon atoms, means a derivative of an aromatic cyclic hydrocarbon such as a phenyl, naphthyl, phenanthrenyl radical or a derivative of a condensed, bicyclic or tricyclic hydrocarbon containing a benzene ring such as indanyl, indenyl, dihydronaphthyl , tetrahydronaphthyl or fluorenyl. The coupling was carried out not at the level of the benzene ring. Phenyl was preferred.

Under the term (Het), which represents saturated or unsaturated, aromatic or non-aromatic heterocycles with from 1 to 9 carbon atoms and from 1 to 5 heteroatoms selected from oxygen, nitrogen and sulfur atoms, the following are particularly selected:

- heterocyclic monocyclic radicals, for example thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazonyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, tetrazolyl radicals,

- fused heterocyclic rings, for example benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, naphtho[2,3-b]-thienyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, quinolyzinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, quinolinyl, pteridinyl, carbazolyl, beta-carbolinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, indolinyl, isoindolinyl, imidazopyridyl, imidazopyrimidinyl or also condensed polycyclic systems consisting of the previously defined heterocyclic monocycles such as for example furo[2,3-b]pyrrole or thieno[2,3-b]-furan,

- or saturated heterocycles such as pyrrolidine, piperidine and morpholine.

Under the term (Alk), which represents radicals obtained from saturated or unsaturated, linear, branched or cyclic non-aromatic hydrocarbons, in the case of non-cyclic hydrocarbons, alkyl radicals such as: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl are selected , n-pentyl, n-hexyl, 2-methyl-pentyl, 2,3-dimethyl-butyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethyl-pentyl, 3-ethylpentyl, n -octyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl-3-ethylpentyl, nonyl, 2,4-dimethylheptyl or n-decyl, alkenyl radicals such as: vinyl, propenyl, isopropenyl, allyl, 2 -methylallyl, butenyl, or isobutenyl, or alkynyl radicals such as: ethynyl, propynyl, propargyl, butynyl or isobutynyl, and in the case of cyclic radicals, cycloalkyl radicals such as: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl.

Methyl and ethyl radicals will be preferred. By CO-Alk is preferably meant COCH3 and COEt, by CO-Ar is preferably meant the benzolyl radical, in the case where m is different from zero, (CH2)m-Ar will preferably be a benzyl group.

When R3 and R4 together with the nitrogen atom to which they are connected form a heterocycle, these are particularly mono- or bicyclic heterocycles that optionally contain another heteroatom, chosen between oxygen and nitrogen, and which include the following unsaturated heterocycles: pyrrolyl, imidazolyl, indolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazolinyl, pyrazolinyl, thiazolinyl or more specifically, the following saturated heterocycles:

[image]

In the case when different Alk, Ar, Het groups, as well as heterocycles obtained from R3 and R4 attached to nitrogen, are substituted, they will be especially substituted with the following radicals:

- halogen, namely fluorine, chlorine, bromine or iodine, alkoxy such as: methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, amino, alkylamino, such as methylamino or ethylamino, dialkylamino such as dimethylamino, diethylamino, methylethylamino, wherein each of these dialkylamino radicals is optionally in oxidized form, aminoalkyl such as aminomethyl or aminoethyl, dialkylaminoalkyl such as dimethylaminomethyl or ethyl, dialkylaminoalkyloxy such as dimethylaminoethyloxy, hydroxyl optionally acylated, acyl such as acetyl, propionyl, butyryl, benzoyl, esterified carboxy such as alkoxycarbonyl for example methoxycarbonyl or ethoxycarbonyl, cyano, trifluoromethyl, aryl such as phenyl, aralkyl such as benzyl , alkyl, alkenyl or alkynyl, wherein the radicals themselves are optionally substituted with halogen, alkyl, alkoxy, alkylthio, amino, alkylamino or dialkylamino radicals indicated in the previous to the text.

Of course, the term "substituted" indicates that one or more identical or different substituents may be present. For example, when the alkyl group is a methyl radical substituent with one or more halogen atoms, these can especially be: CH2Cl, CH2F, CHF2 and CF3.

In the case of (Het), the substitution can take place on the NH or carbon atom.

Of course the values of R1, R2, R3 and R4, as well as n, m and m' are independent of each other.

The invention naturally also relates to salts of compounds represented by formula (I), such as, for example, salts obtained by the action of mineral or organic acids on an amine. These can be the following acids: chloride, bromide, nitric, sulfate, phosphate, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkane sulfonic, such as methane or ethane sulfonic acids, arylsulfonic, such as benzene or paratoluene sulfonic acids and arylcarboxylic. When the compounds represented by formula (I) contain an acid group, the invention extends to salts of alkali metals, alkaline earth metals or ammonia, optionally substituted.

The subject of the invention is obviously the compounds represented by the general formula (I), as defined earlier, as well as their salts, where X is a fluorine atom in the alpha position, and the dashed line does not represent a double bond (ring D of a saturated steroid).

The subject of the invention is also particularly the compounds represented by the general formula (I), as defined in the earlier text, as well as their salts, where R1 is a hydrogen atom, R2 is a methyl radical, Z is either a hydrogen atom or a chlorine atom, Y represents an atom oxygen, and dashed lines do not represent a double bond.

A particularly emphasized subject of the invention are compounds with the general formula (I), as defined in the earlier text, as well as their salts, where R3 and R4, whether identical or different, represent an alkyl radical with from 1 to 6 carbon atoms, or R3 and R4 together with the nitrogen atom to which they are attached form one of the following saturated heterocycles:

[image]

A particularly emphasized subject of the invention are also the compounds represented by the general formula (I), as defined in the earlier text, as well as their salts, where X is a fluorine atom in the alpha position, R1 is a hydrogen atom, R2 is a methyl radical, Y is an oxygen atom, Z is a hydrogen atom or a chlorine atom, n is equal to the numbers 2 or 3, R3 and R4, whether identical or different, represent an alkyl radical containing from 1 to 6 carbon atoms, or R3 and R4 together with a nitrogen atom to which are bonded to form one of the following saturated heterocycles:

[image]

and the dashed line does not represent a double bond.

Finally, the subject of the invention are the compounds shown by formula (I) as well as their salts with acids, the names of which are as follows:

- 17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol

- 17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol-hydrochloride

- 17-alpha-fluoro-11-beta-[4-[2-(1-diethylamino)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol

- 17-alpha-fluoro-11-beta-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol

- 4-chloro-17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol

- 17-iodo-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10),16-tetraen-3-ol

- 17-alpha-fluoro-11-beta-[4-[2-(4-methyl-1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol-hydrochloride

- 17-alpha-fluoro-3-methoxy-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene

- 17-alpha-fluoro-3-methoxy-11-beta-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene

- 17-alpha-fluoro-3-methoxy-11-beta-[4-[2-(diethylamino)ethoxy]phenyl]-estra-1,3,5(10)-triene

- (11-beta)-17-chloro-11-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10),16-tetraen-3-ol

- 17-alpha-chloro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol

- 17-alpha-iodo-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10),16-tetraen-3-ol-hydrochloride

- 17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol-lactate.

The subject of the invention is also a process for the preparation of compounds represented by formula (I), as defined earlier, in which the compound represented by formula (II)

[image]

wherein R 2 and Z are as defined earlier, RA represents one of the following groups:

[image]

in which Y, n, R3 and R4 are defined earlier, and Hal represents a halogen atom, is the subject of action, if suitable after protection and/or activation of the OH group,

either a) a reducing agent of the keto group at position 17, with the purpose of achieving the compound shown by formula (IIIa):

[image]

b) and then halogenating agents in order to obtain the compound shown by formula (I'a):

[image]

which corresponds to certain compounds shown by formula (I), when RA represents -Ph-Y-(CH2)n-NR3R4,

or a) hydrazine in order to obtain the compound represented by formula (IIIb):

[image]

b) and then from a halogenating agent in order to obtain the compound shown by formula (I'b):

[image]

which corresponds to certain compounds shown by formula (I), when RA represents -Ph-Y-(CH2)n-NR3R4,

compounds represented by formulas (II), (IIIa), (IIIb), (I'a) or (I'b), in protected or unprotected form, were subjected, if it was desirable or necessary, to one or more of the following reactions :

- removing the protection from the protected OH group or groups,

- acylation/alkylation of the OH group or groups,

- the action of HNR3R4, optionally in salt form, when RA represents -Ph-Y-(CH2)n-Hal or an activated group -Ph-Y-(CH2)n-OH.

- salification.

The reduction of the 17-keto group to an alcohol was carried out according to a standard procedure, especially by the action of an alkaline borohydride such as sodium borohydride in methanol or ethanol or by the action of aluminum or lithium tetrahydride.

This reduction allows the preferred alcohol to be obtained at the 17-beta position.

The halogenation reaction, which follows, is preferably carried out using a reagent such as XSO2C4F9 in the presence of a base such as DBU (diazabicycloundecane), X is preferably fluorine. Other halogenation methods known to those skilled in the art may also be used.

When the hydroxy group of the starting product is in the beta position, an inversion of the configuration is observed during nucleophilic substitution, and this process (halogenation reagent: perfluoro-1-butane-sulfonylfluoride (FSO2C4F9)) reliably yields the compounds shown by formula (I) or (I 'a) with fluorine at the 17-alpha position.

The reaction with hydrazine is preferably carried out in the presence of a base such as triethylamine, and the subsequent halogenation is carried out with X 2 in a basic medium, especially with I 2 .

The activation of alcohols means in particular the introduction of mesylate, tosylate or triflate, which promote the nucleophilic substitution of the amine HNR3R4 in the compounds shown by formulas (II), (IIIa), (IIIb), (I'a), (I'b) where R3 represents -Ph-Y-(CH2)n-OH group.

The formation of mesylate, tosylate and triflate from the corresponding alcohols is carried out in the presence of a base such as triethylamine. Replacement of the alcohol with a halogen atom, according to the usual procedures for this, can also be previously considered.

Protection and deprotection reactions were carried out by standard procedures known to those skilled in the art. Their complete overview is contained in the following publication: Protective groups in organic synthesis, T.W. Greene, John Wiley & sons (1981).

The protecting group P (OH → OP) can be an alkyl radical containing 1 to 4 carbon atoms, a benzyl group, a tetrahydropyranyl group, RCRDRESi a group in which RC, RD and RE, either identical or different, each independently represent an alkyl radical which contains from 1 to 4 carbon atoms or a phenyl group. These are especially Si(Me)2CMe3 or -Si(Ph)2CMe3 or -SiMe3 groups.

As an example, the deprotection reaction (OP → OH at position 3) when P is a tetrabutyldiphenylsilyl group can be carried out by activating tetrabutylammonium fluoride in solution with tetrahydrofuran. The same is the case when P represents SO2C4F9 followed by a fluoridation reaction.

When P is a tetrahydropyranyl group, deprotection is carried out in the presence of an acid in an alcoholic solvent, preferably by the action of hydrochloric acid in methanol.

The action of the compound represented by the formula R3R4NH on the compounds represented by the formulas (II), (IIIa), (IIIb), (I'a), (I'b), where R2 represents -Ph-Y-(CH2)n-OH or - Ph-Y-(CH2)n-Hal group, was carried out under standard conditions for nucleophilic substitution, especially in the presence of an aprotic solvent such as tetrahydrofuran. When OH is activated, these are especially: OSO2CH3, OSO2-Ph-pMe, OS2CPh3.

Alkylation or acylation reactions of the OH group at position 3 as well as salification reactions are carried out by standard procedures, known to persons skilled in the art.

The compounds of the general formula (I) as well as their salts with pharmaceutically acceptable acids have particularly estrogenic, anti-estrogenic and proliferative activity.

Therefore, the compounds represented by formula (I) can be used in the treatment of disorders associated with hypofolliculinia, for example absence of menstruation, painful menstruation, recurrent miscarriages, premenstrual disorders, in the treatment of certain estrogen-dependent pathologies such as adenoma or prostate cancer, breast cancer and their metastases or in the treatment of benign breast tumors, as an anti-uterotrophic agent as well as in the replacement treatment of menopause or perimenopause.

The symptoms and consequences associated with menopause more specifically mean: fever, sweating, vaginal atrophy and dryness, urinary symptoms, and in the long term, reduction of bone mass and increased risk of fractures, and loss of cardiovascular protection provided by estrogens.

The compounds represented by formula (I) as well as their salts with pharmaceutically acceptable acids or bases can be particularly used in the prevention or treatment of osteoporosis.

The compounds of formula (I) as well as their salts with pharmaceutically acceptable acids or bases may also be used in the prevention or treatment of osteoporosis in humans.

They can also be used to prevent or treat secondary osteoporosis (eg cortisone-related or immobilization-related).

The compounds represented by formula (I) as well as their salts with pharmaceutically acceptable acids or bases show particularly distinct estrogenic activity.

By uncoupled estrogenic activity, we mean estrogenic activity at the level of the bones while showing only minimal activity at the level of the uterus, which is why endometrial proliferation does not occur (much less activity compared to estradiol).

In addition, the compounds of the invention have the following advantages:

- They possess anti-estrogenic and/or anti-proliferative activity at the breast level. Unlike estradiol, they do not stimulate the growth of human breast tumor cells and can even inhibit their growth. For this reason, the compounds of the invention have a particular advantage in the treatment of menopause in women at risk of breast cancer (earlier in the family), who are therefore excluded from replacement treatment using estradiol.

They can also be used in the treatment of breast cancer.

- They can lead to a reduction in cholesterol levels to a level equivalent to that induced by the action of estradiol. Because of this, they enhance cardiovascular protection.

- Finally, since the compounds of the invention do not possess estrogenic activity at the level of the uterus, they do not require administration in combination with a progestomimetic compound.

Therefore, the subject of the invention are drugs obtained from compounds represented by formula (I) as well as their salts with pharmaceutically acceptable acids or bases.

A more specific subject of the invention are the compounds shown by formula (I) as well as their salts with pharmaceutically acceptable acids or bases intended for the prevention or treatment of osteoporosis.

The invention also relates to pharmaceutical compositions containing at least one of the previously defined drugs as an active ingredient.

The compounds of formula (I) are used by the digestive, parenteral or local route, for example through the skin. They can be prescribed in the form of plain or coated tablets, gelatin capsules, granules, suppositories, pessaries, preparations for injection, ointments, creams, gels, microspheres, implants, intravaginal rings, patches, which are prepared according to usual procedures.

The active ingredient or ingredients can be incorporated with excipients commonly used in these pharmaceutical compositions, such as talc, gum arabic, lactose, flour, magnesium stearate, coconut butter, aqueous or non-aqueous carriers, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.

Usual doses vary depending on the disease to be treated and the method of administration; for example, when given orally to adults, they can vary from 1 to 1000 mg per day.

The subject of the invention is also the use of compounds represented by formula (I), as previously defined, for the preparation of drugs that have little or no activity at the level of the uterus, intended for the treatment of hormone replacement in menopause or perimenopause, and in particular for use, characterized by the fact that are drugs intended for the prevention or treatment of osteoporosis.

The compounds shown by formula (II) or (IIIa) are compounds known or readily available to a person skilled in the art. More specifically, compounds of formula (II) where Z=H, R 2 =Me and RA=-Ph-Y-(CH 2 )n-Hal are described in International Application WO 93/13123 (compounds of formula II); compounds represented by formula (II) where Z=H, R2=Me and RA=-Ph-Y-(CH2)n-OH are described in European patent 0305242 B1 (compounds represented by formula (III)), compounds represented by formula ( II) where Z=H, R2=Me and RA=-Ph-Y-(CH2)n-NR3R4 are described in European Patent 0097572, French Addition Certificate 2640977 or European Patent 0305242.

The compounds represented by formula (II) in which Z represents a halogen atom are described in the international application WO 9845316, and are prepared from the compound represented by formula (IV):

[image]

by the action of a halogenating reagent with the aim of obtaining the compound represented by formula (V):

[image]

The compound (V) is subjected to the action of an aromatizing reagent with ring A, and then to the action of a base in order to obtain the compound represented by the formula (II) where Z represents a halogen atom.

The action of a halogenating reagent such as N-bromosuccinimide or N-chloromosuccinimide on the compounds represented by formula (IV) is specifically carried out in the presence of a dipolar aprotic solvent such as dimethylformamide.

The aromatization reaction followed by the saponification reaction (base action) was carried out according to standard procedures described in European patent 0097572. A mixture of acetic anhydride and acetyl bromide was preferably used as an aromatization agent, after which a base such as soda in methanol was used as a saponification agent. .

The subject of the invention are also the compounds shown by formulas (I'a), (IIIb) and (I'b) as intermediate products.

The following examples illustrate the invention, but do not limit it.

Solvents described in the examples: AcOEt (ethyl acetate), TEA (triethylamine), CH2Cl2 (dichloromethane), CHCl3 (chloroform), MeOH (methanol), NH4OH (ammonium hydroxide), iPrOH (isopropyl alcohol).

EXAMPLE 1: 17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol

Stage A: Reduction

11-beta-[4-(iodoethoxy)phenyl]estra-1,3,5(10)-triene-3,17-beta-diol

76 mg of sodium borohydride was added at 0°C to a solution of 516 mg of 3-hydroxy-11-beta-[4-(2-iodoethoxy)phenyl]estra-1,3,5(10)-trien-17-one prepared according to according to the procedure described in WO 93/13123 in 5 ml of MeOH and 5 ml of THF, and stirring was carried out for 5 minutes at that temperature, and then for 1 hour and 30 minutes at ambient temperature. 20 ml of 0.1 N HCl was then added, and crystallization was observed. 460 mg of the expected product was obtained.

Rf AcOEt/TEA 95/5 = 0.67

NMR (CDCl3, 300 MHz)

7.01 and 6.61 (4H, 2d, aromatic H at position 11); 6.79 (1H, d, H1); 6.68 (1H, d, H4); 6.51 (1H, dd, H2); 4.11 (2H, t, CH2O); 3.94 (1H, bt, H11); 3.72 (1H, bt, H17); 3.33 (2H, t, CH2I); 0.37 (3H, s, 18-Me).

Stage B: Fluorination

17-alpha-fluoro-11-beta-[4-(2-iodoethoxy)phenyl]-estra-1,3,5(10)-trien-3-ol-nonanefluorobutanesulfonate.

0.45 ml of DBU, and then 0.20 ml of perfluoro-1-butane-sulfonyl-fluoride (FSO2C4F9) were added at 0°C under nitrogen to a suspension of 518 mg of the steroid prepared in step A in 5 ml of toluene and 1 ml of dichloromethane, and the resulting solution was kept at ambient temperature for 30 minutes. The reaction medium was then poured into 20 ml of water, extracted with ethyl acetate, washed, dried and evaporated under reduced pressure, resulting in 565 mg of crude product which was purified by chromatography on Lichrosorb RP18, eluting with a mixture of acetonitrile and water in a ratio of 85 /15. 350 mg of the expected product was obtained.

Rf CH3CN/H2O 85/15 = 0.47 on LKC18F (Whatman)

Melting point = 110°C

NMR (CDCl3, 250 MHz)

7.00 (2H, m, H1 and H4); 6.93 and 6.63 (4H, 2d, AA ́BB ́, aromatic H at position 11); 6.82 (1H, dd, H2); 4.44 (1H, dd, J1 = 55.5 Hz J2 =5 Hz, H17); 4.14 (2H, t, CH2O); 4.03 (1H, m, H11); 3.35 (2H, t, CH2I); 0.23 (3H, d, J = 2 Hz, CH3).

Stage C: Introduction of amine followed by deprotection.

0.4 ml of piperidine was added to the steroid solution prepared in the earlier stage in 3 ml of THF, the reaction medium was refluxed for 2 hours after which, after cooling, it was poured into 10 ml of water, extracted with ethyl acetate, washed, dried and evaporated under reduced pressure to give 320 mg of the expected crude product. After dissolving in 30 ml of THF, 2 ml of tetrabutylammonium fluoride was added, which was followed by heating for 7 hours at reflux temperature. After cooling, the reaction medium was poured into 20 ml of water saturated with sodium bicarbonate, extracted with ethyl acetate, washed, dried and evaporated under reduced pressure. The obtained 405 mg of crude product was purified by chromatography on silica gel eluting with a mixture of AcOEt and TEA in a ratio of 95/5. 160 mg of the expected pure product was obtained.

Rf AcOEt/TEA 95/5 0.31 on SiO2F254 Merck.

Melting point = 216°C

NMR (CDCl3 300 MHz)

6.95 and 6.48 (4H, 2d, AA ́BB ́, aromatic H at position 11); 6.79 (1H, d, H1); 6.48 (1H, d, H4); 6.39 (1H, dd, H2); 4.44 (1H, dd, J = 56 Hz and 5 Hz, H17); 3.99 (1H, bt, H11); 4.26 and 3.99 (2H, 2m, CH2O), 1.65 and 1.46 (6H, m, CH2 at γ and β position of piperidine); 1.20 to 3.20 (20H, m skeleton H + CH2N and CH2 at the α position of the piperidine); 0.22 (3H, d, J = 2 Hz, CH3).

IR (CHCl3)

- OH 3597 cm-1 + assocd

- aromatic 1608, 1582, 1512, 1503 cm-1

EXAMPLE 2: 17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy)phenyl]-estra-1,3,5(10)-trien-3-ol hydrochloride

2 ml of a 4 N solution of HCl in ethyl acetate was added to a solution of the fluorinated compound from Example 1 in 10 ml of ethyl acetate at 0 to 5°C, and crystallization occurred. 1.6 g of white crystals were obtained.

Rf ACOEt/TEA 95/5 = 0.21 on SiO2F254 Merck.

Melting point = 216°C

NMR (CDCl3 300 MHz)

6.95 and 6.43 (4H, 2d, AA ́BB ́, aromatic H at position 11); 6.79 (1H, d, H1); 6.66 (1H, d, H4); 6.59 (1H, dd, H2); 4.43 (1H, dd, J = 56 Hz and 5 Hz, H17); 3.99 (1H, bt, H11); 4.26 and 3.87 (2H, 2m, CH2O); 3.48 (mobile 1H, NH+); 2.8 to 3.25 (2H, m, CH2N+); 0.22 (3H, d, J = 2 Hz, CH3).

IR (CHCl3)

- OH 3598 cm-1 + assocd

- NH+ absorption

- aromatic 1610, 1582, 1512 cm-1

EXAMPLE 3: 17-alpha-fluoro-11-beta-[4-[2-(1-diethylamino)ethoxy)phenyl]-estra-1,3,5(10)-trien-3-ol

The procedure was carried out as in example 1, but with the use of diethylamine instead of piperidine during stage C, 0.141 g of the expected product was obtained.

Rf AcOEt/Et3N 99/1 = 0.15 on SiO2F254 Merck.

NMR (CDCl3 300 MHz)

0.24 (d, CH3 at position 18); 1.05 (t, CH3CH2N); 2.64 (q, CH 3 CH 2 N); 2.83 (t, O-CH2-CH2N); 3.95 (t, CH2O); 4.00 (bt, H11); 4.44 (dd, J = 56 Hz and 5 Hz, H17); 6.32 (d, H1), 6.38 (dd, H2); 6.53 (d, H4); 6.57 and 6.96 (AA ́BB ́, aromatic H at position 11);

EXAMPLE 4: 17-alpha-fluoro-11-beta-[4-[2-(1-pyrrolidinyl)ethoxy)phenyl]-estra-1,3,5(10)-trien-3-ol

The procedure was carried out as in example 1, but with the use of pyrrolidine instead of piperidine during step C. 0.049 g of the expected product was obtained.

Rf AcOEt/Et3N 95/5 = 0.18 on SiO2F254 Merck.

NMR (CDCl3 300 MHz)

0.28 (d, CH3 at position 18); 2.70 (m, pyridine); 3.03 (t, CH2N); 3.98 (t, CH2O); 4.45 (dd, H17): 6.37 (dd, H2); 6.41 (d, H4); 6.50 and 6.96 (AA ́BB ́, aromatic H at position 11); 6.78 (d, H1)

EXAMPLE 5: 4-chloro-17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy)phenyl]-estra-1,3,5(10)-trien-3-ol

Step A: Protection of 3-hydroxy-4-chloro-3-[[dimethyl(2,2-dimethyl)ethyl)silyl]oxy]-11-beta-[4-[2-(1-piperidinyl)ethoxy)phenyl] -estra-1,3,5(10)-trien-3-one.

1.3 g of t-butyldimethylsilyl chloride was added to a solution of 4-chloro-3-hydroxy-11-beta-[4-[2-(1-piperidinyl)ethoxy)phenyl]-ester-1,3,5(10) -trien-3-one prepared by the action of NCS on the corresponding Δ 4-5 9-10, 3-one derivative, which was followed by the aromatization reaction of ring A in 30 ml of CH2Cl2. The reaction mixture was cooled to 0°C, after which 1.13 ml of TEA was added dropwise. After 5 minutes at 0°C, the reaction mixture was brought to ambient temperature and maintained there for 3 hours, which was followed by pouring into 100 ml of water. After drying, the organic phase was evaporated under reduced pressure to obtain 4.55 g of crude product, which was purified by chromatography on silica gel, eluting with a mixture of AcOEt and

TEA in the ratio 98/2. 2.68 g of the expected pure product was obtained.

Rf AcOEt/TEA 90/10 = 0.58 on SiO2F254 Merck.

IR (CHCl3)

C=O 1733 cm-1

aromatic C-H 2936 - 2859 cm-1

Stage B: Reduction

4-chloro-3-[[dimethyl-(2,2-dimethylethyl)silyl)oxy)-11-beta-[4-[2-(1-piperidinyl)ethoxy)phenyl]-estra-1,3,5( 10)-trien-3-ol.

189 mg of NaBH4 was added to a solution of the steroid, obtained in the previous step, in 15 ml of methanol, the mixture was cooled using an ice bath and stirred for 5 minutes at a temperature of 0 to 5°C, and then for another 30 minutes at ambient temperature. The reaction mixture was poured into 100 ml of water, extracted with ethyl acetate, washed, dried and evaporated under reduced pressure. 1.5 g of the expected product was obtained.

Rf AcOEt/TEA 90/10 = 0.40 on SiO2F254 Merck.

Stage C: Fluoridation and subsequent deprotection

- Fluoridation

0.90 ml of DBU and 0.04 ml of perfluorobutane-sulfonyl-fluoride were added at ambient temperature and in a nitrogen atmosphere to a solution of 596 mg of steroid, obtained in the previous step, in 5 ml of toluene and 1 ml of CH2Cl2, and the reaction mixture was mixed during 2 hours. After pouring into 20 ml of water, extraction was carried out using dichloromethane, followed by washing, drying and evaporation under reduced pressure. 1.23 g of crude product was obtained, which was purified by chromatography on silica gel, eluting with a mixture of AcOEt and TEA in a ratio of 98/2. 0.6 g of the fluorinated product protected at position 3 was isolated.

- Removal of protection

2 ml of Bu4NF was added to a solution of the fluorinated product in 3 ml of THF, and the mixture was heated at reflux temperature for 4 hours, after which it was cooled and poured into 20 ml of water. After extraction with dichloromethane, washing and drying, evaporation was carried out under reduced pressure, until a dry extract was obtained, which was purified by chromatography on Lichrosorb RP18, eluting with a mixture of MeOH/H2O/TEA in the ratio 90/9/1. 65 mg of the expected product was obtained.

Rf MeOH H2O/TEA 90/9/1 = 0.23 on LKC18F (Whatman)

NMR (CDCl3 300 MHz)

6.91 and 6.61 (4H, 2d, AA ́BB ́, aromatic H at position 11); 6.80 (1H, d, H1); 6.61 (1H, d, H2); 4.34 (1H, dd, J = 5 Hz and 55.5 Hz, H17); 3.98 (1H, masked, H11); 3.98 (2H, t, CH2O); 2.70 (2H, t, CH2N); 2.47 (4H, m, 2CH2 at the α position of the piperidine nitrogen); 1.58 (4H, m, 2CH2 at the β position of the piperidine nitrogen); 1.44 (2H, m, 1CH2 at the γ position of the piperidine nitrogen); 0.22 (3H, d, J = 2.5 Hz, 18-Me).

IR (CHCl3)

OH 3537 cm-1

Aromatic 1608, 1581, 1512 cm-1

For use as in the previous examples, the following products are prepared:

EXAMPLE 6: 17-iodo-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10),16-tetraen-3-ol.

Rf: 0.33 (AcOEt-TEA 90-10).

IR (CHCl3)

OH: 3600 cm-1; aromatic: 1609, 1580, 1512 cm-1.

NMR (CDCl3, 300 MHz)

0.46: (s, CH3 at position 18); 3.95: (m, CH2O and H11); 6.11: (H16); 6.36: (dd, H2); 6.44: (d, H4); 6.71: (d, H1); ≈6.50 to ≈6.94: (aromatic at position 11).

EXAMPLE 7: 17-alpha-fluoro-11-beta-[4-[2-(4-methyl-1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol.

Rf: 0.22 (AcOEt-TEA 99-1).

IR (CHCl3)

OH: 3599 cm-1; aromatic: 1610, 1581, 1512 (F) cm-1

NMR (CDCl3, 300 MHz)

0.26: (s, CH3 at position 18); 0.90: (d, CH3 at position 4 of piperidinyl); ≈3.97: (m, CH2O and H11); 4.43: (dd, H17); 6.38: (dd, H2); 6.46: (d, H4); 6.80: (d, H1); ≈6.50 to ≈6.95: (aromatic at position 11).

EXAMPLE 8: 17-alpha-fluoro-11-beta-[4-[2-(4-methyl-1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol- hydrochloride.

Melting point = 200°C

Rf: 0.15 (AcOEt-TEA 99-1).

NMR (CDCl3, 300 MHz)

0.16: (s, CH3 at position 18); 0.90: (d, CH3 at position 4 of piperidinyl); 3.98: (bs, H11); 4.25: (bs, CH2O); 4.45: (dd, H17); 6.31: (dd, H2); 6.48: (d, J=2 H4); 6.71: (d, H1); 6.71 to 7.02: (aromatic at position 11); 8.97 (s, OH at position 3).

EXAMPLE 9: 17-alpha-fluoro-3-methoxy-11-beta-[4-[2-(4-methyl-1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene.

Rf: 0.23 (MeOH-H2O-TEA 94-5-1).

IR (CHCl3)

absence of OH; aromatic: 1610, 1578, 1512, 1501 cm-1

NMR (CDCl3, 300 MHz)

0.22: (s, CH3 at position 18); 1.58: (m) and 2.47 (m): piperidine; 2.70: (t, CH2-N): 3.73: (s, CH3-O); 3.98: (t, CH 2 O); 4.43: (dd, H17); 6.50: (dd, H2); 6.64: (bs, H4); 6.88: (d, H1); ≈6.62 to ≈6.97: (aromatic at position 11).

EXAMPLE 10: 17-alpha-fluoro-3-methoxy-11-beta-[4-[2-(4-methyl-1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene.

Melting point = 132°C.

Rf: 0.21 (MeOH-H2O-TEA 94-5-1).

IR (CHCl3)

aromatic: 1610, 1578, 1512, 1501 cm-1

NMR (CDCl3, 300 MHz)

0.22: (s, CH3 at position 18); 1.78: (m) and 2.58 (m): pyrrolidine; 2.83: (t, CH2-N): 3.73: (s, CH3-O); 3.99: (t, CH2O); 4.43: (dd, H17); 6.50: (dd, H2); ≈6.65: (H4); 6.89: (d, H1); ≈6.62 to ≈6.97: (aromatic at position 11).

EXAMPLE 11: 17-alpha-fluoro-3-methoxy-11-beta-[4-[2-(diethylamino)-ethoxy]-phenyl]-estra-1,3,5(10)-triene.

Rf: 0.20 (MeOH-H2O-TEA 94-5-1).

IR (CHCl3)

aromatic: 1610, 1578, 1512, 1501 cm-1

NMR (CDCl3, 300 MHz)

0.22: (s, CH3 at position 18); 1.04: (t) and 2.61 (q): N-Et2; 2.82: (t, CH2-N): 3.73: (s, CH3-O); 3.94: (t, CH 2 O); 4.43: (dd, H17); 6.49: (dd, H2); 6.64: (d, H4); 6.88: (d, H1); ≈6.62 to ≈6.96: (aromatic at position 11).

m skeleton H + CH2N and CH2 at the α position of piperidine); 0.22 (3H, d, J = 2 Hz, CH3).

EXAMPLE 12: (11-beta)-17-chloro-11-[4-[2-(1-piperidinyl)-ethoxy]phenyl]-estra-1,3,5(10),16-tetraen-3-ol .

Rf: 0.25 (CH2Cl2-MeOH-NH4OH 95-5-0.5).

NMR (CDCl3, 300 MHz)

0.60: (s, CH3 at position 18); ≈4.01: (m, CH2O and H11): 5.60: (bd, H16); 6.38: (dd, H2); 6.45: (d, H4); 6.70: (d, H1); ≈6.50 to ≈6.93: (aromatic at position 11).

EXAMPLE 13: 17-chloro-11-beta-[4-[2-(1-piperidinyl)-ethoxy]-phenyl]-estra-1,3,5(10)-trien-3-ol.

Rf: 0.10 (CH2Cl2-MeOH-NH4OH 94-5-0.5).

NMR (CDCl3, 300 MHz)

0.41: (s, CH3 at position 18); ≈3.98: (m, CH2O and H11 and H17): 6.39: (dd, H2); 6.48: (H4); 6.79: (d, H1); ≈6.48 to ≈6.94: (aromatic at position 11).

EXAMPLE 14: 17-iodo-11-beta-[4-[2-(4-methyl-1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10),16-tetraen-3-ol- hydrochloride.

Melting point = 260°C.

Rf: 0.33 (AcOEt-TEA 90-10).

NMR (DMSO, 300 MHz)

0.29: (s, CH3 at position 18); 4.02: (bt, H11); 4.25: (bs, CH 2 O): 6.15: (bs, H 16 ); 6.29: (dd, H2); 6.48: (d, H4); 6.64: (d, H1); ≈6.73 to ≈7.01: (aromatic at position 11); 8.94 to ≈9.78: mobile H.

EXAMPLE 15: 17-alpha-fluoro-11-beta-[4-[2-(4-methyl-1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol- lactate.

Melting point = 138°C.

Rf: 0.22 (AcOEt-TEA 99-1).

NMR (CDCl3, 300 MHz)

0.22: (d, CH3 at position 18); ≈3.15: (CH2N); ≈3.94: (m, CH2-O); ≈3.98: (m, H11); 4.43: (dd, H17); 6.42: (dd, H2); 6.78: (d, H1); ≈6.48 to ≈6.97: (aromatic at position 11); 1.36 (d) and 4.09 (m): lactate.

Pharmacological tests

Effect on breast cell proliferation

The proliferative activity of the molecule was studied in relation to the activity of estradiol in cultured human MCF-7 breast cells.

In order to show the stimulation effect of estradiol and/or the tested molecules, the medium of the maintained cell culture (rich in growth factor and steroids) was replaced with a depleted medium, which, among other things, does not contain steroids (DMEM with 5% serum without steroids and without phenol redness). The cells were subjected to this treatment for 2 days before the start of the test. After the studied product was present in the culture for 7 days, cell proliferation was assessed from DNA determination. In each assay, the effect of estradiol at 10-10 M (cell growth in the presence of estradiol minus cell growth in the presence of solvent) determines 100% stimulatory activity. The activity of the molecules was estimated from comparison with this internal control. Molecules that stimulated cell growth identical to that observed in the solvent alone were classified as "inactive", those that stimulated less cell growth compared to the growth observed in the solvent were classified as "inhibitors".

[image]

Study of the effect of the product on the bones of ovariectomized female rats at the age of 3 months

The compounds were tested in order to determine their effect on bone mass, and on the formation and resorption activity in the ovariectomized rat model at the age of 3 months. The animals were treated in a preventive manner.

Animals:

[image]

Products:

1 - Test product: product from example 1.

* carrier(s): corn oil, 0.5% methylcellulose

* number of administrations: once/day; 5 days/week for 4 weeks

* method of administration: oral method for the product

* volumes: 5 ml/kg (p.o.)

* period between last injection and sacrifice: 24 hours

* number of benefits: 20

2 - Recommended product: 17β-estradiol was administered subcutaneously in a dose of 0.1 or 0.01 mg/kg/d in a solution of a mixture of corn oil and benzyl alcohol (99:1, v/v) with a volume of 0.2 ml / kg.

Experimental protocol

Animals

The study was conducted with ovariectomized female rats at the age of 3 months. The animals were kept in an air-conditioned room (temperature 20°C ± 2°C) and sorted into cages in groups of 4. The animals received ad libitum, demineralized water and compressed food (tablets: AO4CR-10 UAR).

Surgery

Three-month-old female rats weighing approximately 250 g were ovariectomized under anesthesia with Imalgene 1000 administered intraperitoneally (i.p.) at a dose of 100 mg/kg and under a volume of 1 ml/kg. They also received Nembutal (3 mg/kg i.p. under a volume of 0.3 ml/kg).

After the lateral incision, the skin and muscles are separated. Removal of the ovaries was performed after ligation of the fallopian tubes.

"SHAM" control rats were anesthetized under the same conditions. After incising the skin and muscles, each ovary was removed and then replaced in situ.

Treatment

The effects of the products are determined by preventive treatment. They were administered immediately after ovariectomy. The animals are arranged in groups of 8.

Group 1: "SHAM" control rats received vehicle or vehicles.

Group 2 "OVX" control rats received vehicle or vehicles.

Groups X: "OVX" rats received individually defined doses of the product or products being tested.

Blood samples

After 4 weeks (the duration of the study), the animals were decapitated using a guillotine. Sera collected after centrifugation were stored at -20°C.

The balance of lipids in serums will be established from the determination of the total amount of cholesterol, triglycerides and phospholipids in an aliquot of 500 l of serum. The decrease in serum cholesterol level is expressed in relative % compared to the level obtained in ovariectomized animals that received only solvent.

Organ samples

After sacrificing the animals, the following organs were removed:

- genital tract

The uteruses were removed. They are weighed. The increase in weight is expressed in % of the weight of the uterus of ovariectomized animals that received only solvent.

- at the bone level:

Bone mass (BMD or bone mineral density) was measured using two-photon dual-energy X-ray absorptiometry (DEXA). Measurements were made on cut bones cleaned of all soft tissue. BMD (bone mineral density) was measured on the whole bone as well as on the metaphyseal part at the level of the proximal end of the left tibia. This zone is defined as the area richest in trabecular bones; and as a result, is most sensitive to variations in bone volume and bone mineral density.

The result is expressed in % according to the following formula:

Tested product BMD -OVX BMD × 100

SHAM BMD - OVX BMD

[image]

Claims (17)

1. Compounds represented by the general formula (I): [image] indicated that: R1 represents a hydrogen atom, (CH2)m-Ar, (CO)-Ar, (CH2)m-Alk or (CO)-Alk radical, R2 represents a radical obtained from a straight or branched, saturated or unsaturated hydrocarbon containing 1 to 6 carbon atoms X represents a halogen atom, Y represents a single bond, O, NH, S, SO, or SO2, Z represents a hydrogen atom or a halogen atom, n is equal to the numbers 2, 3, 4 or 5, or R3 and R4, identical or different, represent a hydrogen atom, (CH2)m'-Ar, (CH2)m'-Het or (CH2)m'-Alk group, or R3 and R4 form together with a nitrogen atom, with which are linked, aromatic or non-aromatic, saturated or unsaturated mono- or polycyclic heterocycle with 3 to 15 members optionally containing 1 to 3 additional hetero atoms selected from oxygen, sulfur and nitrogen, unsubstituted or substituted, Ar represents a carbocyclic aryl group containing 6 to 18 carbon atoms, Het represents a saturated or unsaturated aromatic or non-aromatic heterocycle containing from 1 to 9 carbon atoms and from 1 to 5 heteroatoms selected from oxygen, nitrogen or sulfur atoms, Alk represents a radical obtained from saturated or unsaturated, linear, branched or cyclic, non-aromatic hydrocarbon and contains from 1 to 12 carbon atoms, radicals Ar, Het or Alk can be substituted or unsubstituted, m and m' represent the numbers 0, 1, 2 or 3, dashed lines represent a possible double bond, as well as their salts with added bases or acids. 2. Compounds shown by the general formula (I) as defined in claim 1, as well as their salts, indicated that X is a fluorine atom in the alpha position, and the dashed line does not represent a double bond. 3. Compounds represented by the general formula (I) as defined in claim 1 or 2, as well as their salts, characterized in that R1 represents a hydrogen atom, R2 is a methyl radical, and Z is a hydrogen atom or a chlorine atom, Y represents an atom oxygen, and the dashed line does not represent a double bond. 4. Compounds represented by the general formula (I) as defined in any of claims 1 to 3, as well as their salts, characterized in that: or R3 and R4, identical or different, represent an alkyl radical with 1 to 6 carbon atoms, a hydrogen atom, or R3 and R4 together with the nitrogen atom, to which they are attached, form one of the following saturated heterocycles: [image] 5. Compounds represented by the general formula (I) as defined in any of claims 1 to 4, as well as salts thereof, characterized in that X is a fluorine atom in the alpha position, R1 is a hydrogen atom, R2 is a methyl radical, Y is an oxygen atom, Z is a hydrogen atom or a chlorine atom, n is equal to the numbers 2 or 3, or R3 and R4, whether identical or different, represent an alkyl radical containing from 1 to 6 carbon atoms, or R3 and R4 together with the nitrogen atom to which they are attached form one of the following saturated heterocycles: [image] and the dashed line does not represent a double bond. 6. Compounds according to any of claims 1 to 5, characterized in that: - 17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol - 17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol-hydrochloride - 17-alpha-fluoro-11-beta-[4-[2-(1-diethylamino)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol - 17-alpha-fluoro-11-beta-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol - 4-chloro-17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol - 17-iodo-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10),16-tetraen-3-ol - 17-alpha-fluoro-11-beta-[4-[2-(4-methyl-1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol-hydrochloride - 17-alpha-fluoro-3-methoxy-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene - 17-alpha-fluoro-3-methoxy-11-beta-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene - 17-alpha-fluoro-3-methoxy-11-beta-[4-[2-(diethylamino)ethoxy]phenyl]-estra-1,3,5(10)-triene - (11-beta)-17-chloro-11-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10),16-tetraen-3-ol - 17-alpha-chloro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol - 17-iodo-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10),16-tetraen-3-ol-hydrochloride - 17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol. 7. Process for the preparation of compounds represented by formula (I), as defined in claim 1, characterized in that the compound is represented by formula (II) [image] wherein R 2 and Z are as defined earlier, RA represents one of the following groups: [image] in which Y, n, R3 and R4 are as defined earlier, and Hal represents a halogen atom, subjected to action, if appropriate after protection and/or activation of the OH group, either a) reducing agent of the keto group at position 17 in order to achieve the compound shown by formula (IIIa): [image] b) and then halogenating agents in order to obtain the compound shown by formula (I'a): [image] which corresponds to certain compounds shown by formula (I), when RA represents -Ph-Y-(CH2)n-NR3R4, or a) hydrazine in order to obtain the compound represented by formula (IIIb): [image] b) and then halogenating agents in order to obtain the compound shown by formula (I'b): [image] which corresponds to certain compounds shown by formula (I), when RA represents -Ph-Y-(CH2)n-NR3R4, compounds represented by formulas (II), (IIIa), (IIIb), (I'a) or (I'b), in protected or unprotected form, were subjected, if it was desirable or necessary, to one or more of the following reaction: - removing the protection from the protected OH group or groups, - acylation/alkylation of the OH group or groups, - the action of HNR3R4, optionally in salt form, when RA represents -Ph-Y-(CH2)n-Hal or an activated group -Ph-Y-(CH2)n-OH. - salification. 8. The preparation process according to claim 7 of the compounds shown by the general formula (I) as defined in claim 2 where X represents a fluorine atom at position 17 alpha and dashed lines do not represent a double bond, indicated by the fact that the halogenating reagent is perfluoro-1- butane-sulfonyl-fluoride (FSO2C4F9). 9. Compounds represented by the general formula (I) as defined in claim 1, as well as their salts with pharmaceutically acceptable acids and bases, indicated to be used as medicines. 10. Compounds represented by the general formula (I) as defined in any one of claims 2 to 3, as well as their salts with pharmaceutically acceptable acids, indicated to be used as medicines. 11. Compounds as defined in claim 6, as well as their salts with pharmaceutically acceptable acids, indicated to be used as medicines. 12. Pharmaceutical compositions, characterized in that they include one or more drugs as defined in claims 9, 10 or 11. 13. Compounds as new intermediates, characterized by the fact that they are represented by the general formulas (I'a), (IIIb) and (I'b) as in claims 7 or 8. 14. The use of compounds represented by the general formula (I) as defined in claims 1 to 6, indicated by the fact that it is intended for the preparation of drugs for the treatment of hormone replacement in menopause or perimenopause, which have little or no activity at the level of the uterus. 15. Use according to claim 14, characterized in that the drugs are intended for the prevention or treatment of osteoporosis. 16. The drug, as defined in claim 11, characterized in that it is intended for the prevention or treatment of osteoporosis. 17. The drug, as defined in claim 11, characterized in that it is intended for cardiovascular protection.